Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

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dlf
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Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by dlf » Tue 22 Nov 2016 20:26

ORIGINAL RESEARCH ARTICLE (Full text)

Front. Microbiol., 04 November 2016 | http://dx.doi.org/10.3389/fmicb.2016.01744
Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Microcolony B. burgdorferi Persisters Which Are Sterilized by Daptomycin/ Doxycycline/Cefuroxime without Pulse Dosing

Jie Feng, Shuo Zhang, Wanliang Shi and Ying Zhang*
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

http://journal.frontiersin.org/article/ ... 01744/full
Although the majority of Lyme disease patients can be cured, at least 10–20% of the patients continue to suffer from persisting symptoms such as fatigue, muscular and joint pain, and neurologic impairment after standard 2–4 week antibiotic treatment. While the causes for this post-treatment Lyme disease symptoms are unclear, one possibility is due to Borrelia burgdorferi persisters that are not effectively killed by current antibiotics such as doxycycline or amoxicillin used to treat Lyme disease. A previous study showed that four rounds of ceftriaxone pulse dosing treatment eradicated B. burgdorferi persisters in vitro using a relatively young late log phase culture (5 day old). In this study, we investigated if ceftriaxone pulse dosing could also eradicate B. burgdorferi persisters in older stationary phase cultures (10 day old) enriched with more resistant microcolony form of persisters. We found that ceftriaxone pulse dosing could only eradicate planktonic log phase B. burgdorferi spirochetal forms and round body forms but not more resistant aggregated biofilm-like microcolony persisters enriched in stationary phase cultures. Moreover, we found that not all drugs are suitable for pulse dosing, with bactericidal drugs ceftriaxone and cefuroxime being more appropriate for pulse dosing than bacteriostatic drug doxycycline and persister drug daptomycin. We also showed that drug combination pulse dosing treatment was more effective than single drug pulse dosing. Importantly, we demonstrate that pulse dosing treatment impaired the activity of the persister drug daptomycin and its drug combination against B. burgdorferi persisters and that the most effective way to kill the more resistant biofilm-like microcolonies is the daptomycin/doxycycline/ceftriaxone triple drug combination without pulse dosing. Our findings indicate pulse dosing may not always work as a general principle but rather depends on the specific drugs used, with cidal drugs being more appropriate for pulse dosing than static or persister drugs, and that drug combination approach with persister drugs is more effective at killing the more resistant microcolony form of persisters than pulse dosing. These observations may have implications for more effective treatment of Lyme disease. Future studies are required to validate these findings in animal models of B. burgdorferi persistence.

duncan
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by duncan » Tue 22 Nov 2016 20:38

Curiouser and curiouser.

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Wed 30 Nov 2016 19:01

Although the screening of the NCI-DTP library might reveal several drugs that have antibacterial activity for Borrelia, such drugs often are quite toxic for human cells -- as most anti-cancer drugs are. One may be justified in using such drugs for the treatment of cancers in patients that are at or near the terminal stage. However, it is quite a different matter and clearly would be unethical, to use such drugs for the treatment of what some call chronic Lyme disease when (a) there are several antibiotics known to be effective and safe for such a purpose, and (b) especially when there is no supporting evidence to indicate that symptoms reported are in fact due to a persistent Borrelia infection. Obviously, using an anti-cancer drug discovered by such a process to treat patients with chronic Lyme disease would never be approved for antibiotic therapy by a clinical review board, a necessary step to obtain crucial data on efficacy for FDA approval. In short, it would not be ethical to treat people as though they were guinea pigs.The in vitro studies of Zhang et al. have no relevance to the in vivo clinical situation.

duncan
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by duncan » Wed 30 Nov 2016 22:54

Ethics are a funny thing sometimes.

Is it ethical not to try to treat people infected with Lyme that conventional therapy fails? To abandon perhaps as many as 60,000 patients each and every year?

At least some courageous researchers are striving to find cures, as opposed to others who seem content with trying to rewrite history a bit at a time.

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Thu 1 Dec 2016 14:40

Duncan: Tell me, what so courageous about treating people for Lyme disease when there is no objective evidence to prove that they have it and that it is due to a persistent infection? That doesn't make sense. To say it is unethical is a understatement.

Now, let's return to you own situation where you can not provide evidence to PROVE that you have Lyme disease and continue to search for some test (e.g., the Ceres nanotrap assay) that will prove to you -- and those in Lymeland-- that you really have it. If conventional treatment fails to cure such people, doesn't it makes more sense to consider other possible causes for their symptoms?

Incidentally, Klinghardt, at his Sophia Institute of Health, has developed a new PCR urine-based test for the diagnosis of Lyme disease. He reports that of 120 patients examined, all but 2 were positive by his test. That means almost everyone that walks in to be tested is positive for Lyme disease. This new test may be the answer to your prayers, Duncan. He also states that he is able to cure patients after treating them for 6-12 months with his wacko unproven therapies. What more can you ask for............

duncan
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by duncan » Thu 1 Dec 2016 15:23

What I find particularly gratifying is that this study represents a Johns Hopkins effort. :D

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Thu 1 Dec 2016 20:50

Gratifying? Why so? Please explain.

duncan
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by duncan » Thu 1 Dec 2016 21:25

How do the authors put it? "...at least 10-20% of the patients continue to suffer from persistent symptoms..." Why? "...one possibility is due to Borrelia burgdorferi persisters..."

So that's 10-20% of - what is the latest estimate? Upwards of 375,000 in the US alone each year?

Thank goodness courageous researchers like these are out there to not only apparently acknowledge the debacle, but to take steps to try to develop new treatment regimens -- efforts which potentially could help mitigate the surging ranks of those disabled by Borrelia and other tick-borne diseases.

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Thu 1 Dec 2016 22:22

As I have said before -- and repeatedly-- the clinical relevance of the results of the in vitro studies of Zhang et al. remain to be established. There is another explanation that is quite plausible to explain persisters. See the work of Abel zur Wiesch et al. that I have commented on previously. And then there are the ethical issues of using drugs derived from the NCI-DTP library.If one is interested in making progress, it makes more sense to me -- by far-- to explore other causes for the symptoms these patients have.

duncan
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by duncan » Thu 1 Dec 2016 22:34

I wonder what the clinical relevance of, every 12 months, the generating of over 60,000 confirmed Lyme patients - but not cured of symptoms - is.

As to ethics, I'm a bit hazy on how ethical either ignoring or deflecting the fact that conventional treatment fails up to 20% of confirmed Lyme patients would be.

But a study from Johns Hopkins researchers which seems to concede there may be a problem is a big step in the right direction.

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